Project Summary/Abstract: Retinal ganglion cells (RGCs) are the output neurons of the retina. RGCs are particularly vulnerable as they are irreversibly damaged by diverse insults. The loss of RGCs is a leading cause of vision impairment and blindness worldwide. In order to preserve RGCs, extensive research efforts have been devoted to dissecting out the signaling mechanisms underlying RGC death caused by the diverse groups of insults. Understanding the pathways triggered by diverse insults leading to RGC death will facilitate the design of therapeutic strategies to save RGCs. Calcium signaling regulates many aspects of cellular processes and functions. Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in coordinating and executing calcium signals. The exact role of CaMKII in RGC death remains to be determined. We hypothesize that diverse insults to RGCs may perturb CaMKII and its downstream signaling, leading to RGC death. We further reason that modulation of CaMKII activity and the downstream effectors of CaMKII may provide a general protection for RGCs against a wide spectrum of insults. The long-term goal of our research is to understand the molecular mechanisms underlying RGC death, and to develop therapeutic strategies for the protection of RGCs that typically die in a diseased retina such as glaucoma. We propose to investigate the role of CaMKII and the downstream signaling of CaMKII in RGC death induced by three different insults (NMDA excitotoxicity, optic nerve injury, and ocular hypertension) representing acute and chronic insults to RGCs, through the following Aims: Aim 1) We will investigate the role of CaMKII and its downstream signaling in protecting RGC soma and axons from NMDA excitotoxicity. Aim 2) We will investigate the role of CaMKII and its downstream signaling in protecting RGC soma and axons from optic nerve injury. Aim 3) We will investigate CaMKII- mediated RGC protection in microbead occlusion model of ocular hypertension, and examine whether CaMKII- mediated RGC protection restores visual function in both acute and chronic damage models. In summary, the proposed research will help elucidate the role of CaMKII, at the molecular and cellular level, in the degeneration of RGC soma and axons induced by diverse insults representing both acute and chronic damages, and our proposed studies will provide scientific foundation for CaMKII as a therapeutic target for RGC protection and vision restoration.